The hydrogenation of aromatic compounds is a standard reaction in organic chemistry and the resulting products are utilised commercially in many products.
Ring-hydrogenated amino acids and derivatives thereof, as structural mimetics of the natural amino acids valine and isoleucine, are interesting building blocks in peptide chemistry, for example (J. Med. Chem. 1993, 36, 166; Coll. Czech. Chem. Commun. 1984, 49, 712; Coll. Czech. Chem. Commun. 1966, 31, 4563; Synthetic Communications, 1978, 8, 345), and are used in a number of active ingredients, particularly renin inhibitors (e.g. WO 91/07430, EP 438311 and EP 427939) and thrombin inhibitors (e.g. melagatran and ximelagatran, Drugs of the Future 2001, 26, 1155). There is therefore a corresponding level of interest in the economical production of such amino acids on an industrial scale.
One possibility for the production of these compounds is the hydrogenation of corresponding aromatic precursors, many of which are available at a reasonable cost in enantiopure form (e.g. phenylalanine, phenylglycine and tyrosine). However, although the hydrogenation of simple, unsubstituted aromatic hydrocarbons to the corresponding saturated compounds under pressure in the presence of a noble metal catalyst is relatively straightforward, the hydrogenation of substituted aromatics is substantially more difficult. Secondary reactions can occur, such as e.g. a hydrogenolytic cleaving of substituents, particularly if palladium and platinum catalysts are used (Synthetic Communications, 1999, 29, 4327). Detailed investigations of the reactions are therefore necessary in many of these cases in order to optimise the reaction conditions (J. Org. Chem., 1958, 23, 276; Org. Syn., 1947, 27, 21).
An additional problem occurs if the substituent is carrying an asymmetrical C atom (particularly if it is in the benzyl position), since there is always a danger of partial racemisation (Synthetic Communications, 1978, 8, 345; EP 0823416). The racemisation-free hydrogenation of e.g. phenylglycine to cyclohexylglycine is therefore an especially critical reaction.
Several processes for the hydrogenation of phenylglycine, phenylalanine and other amino acids having aromatic substituents are described in the literature. Palladium, PtO2 (Adam's catalyst), platinum, ruthenium and rhodium were used therein as catalysts.
However, as a consequence of the hydrogenolytic cleaving of the benzyl amino group that occurs as a secondary reaction, the hydrogenation of phenylglycine with Pd(OH)2 (Synthetic Communications, 1978, 8, 345) generates only moderate yields. In addition, the cyclohexylglycine produced in this way was partially racemised.
The use of PtO2 as a hydrogenating catalyst is described in a large number of publications. However, in most cases (U.S. Pat. No. 4,788,322; J. Org. Chem., 1988, 53, 873; TH 1992, 48, 307; THL 1996, 37, 1961; TH 1998, 54, 5545) only phenylalanine was hydrogenated, so no conclusion can be drawn about racemisation in the benzyl position. In two cases phenylglycine is also described as an educt (J. Am. Chem. Soc., 1982, 104, 363; Chem. Berichte 1986, 119, 2191). In the second case at least, a partial racemisation of the product is probable because of the specified angle of rotation. Other disadvantages of this method are the relatively long hydrogenation times (18 h) and the use of acetic acid as solvent, since this makes it more difficult to isolate the products.
Platinum itself has also been used as a catalyst (J. Chem. Soc. C, 1968, 531; THL, 1991, 32, 3623), although only the hydrogenation of phenylalanine is described in these cases, so again no conclusion can be drawn about a possible racemisation. In addition, no details are given of yields or of the pressures, reaction temperature and reaction times required. On the basis of the details given in Synthetic Communications, 1999, 29, 4332, however, it must be assumed that these hydrogenation reactions do not proceed particularly advantageously.
Patent EP 0823416 describes the use of a ruthenium catalyst for the hydrogenation of phenylglycine and phenylalanine, although at 65% the yields are moderate and unacceptable on an industrial scale.
Finally, rhodium catalysts have also been used for the hydrogenation of phenylglycine (Synthetic Communications, 1999, 29, 4327). In this case, however, the hydrogenation times (40 h) are very long, despite the use of more than 10 wt. % catalyst. Furthermore, a major disadvantage of the pure rhodium catalyst described here (5% Rh/C) is the high price of rhodium, which is by far the most expensive of the noble metals mentioned here.